Invasive candidiasis is an important medical problem with a high mortality (30-50%) associated with both the health status of patients who are usually people with immunodeficiencies, and with the virulence of the fungus. The fungal species Candida albicans causes half of these diseases. Other species such as Candida parapsilosis, Candida glabrata or Candida tropicalis are important etiological agents because of their increasing frequency and the potential resistance to the antifungal drugs used in the therapy of candidiasis. Candida auris is an emerging species of recent association with human disease with cross resistance to antifungal drugs and the ability to persist in the hospital environment [1]. The early diagnosis of invasive candidiasis is difficult: There are not specific biomarkers for diagnosis and identification by conventional and molecular methods of the species causing the infection is based in the culture of this fungus in suitable mycological media.

Aims: To become familiar with the microbiological laboratory techniques used for the etiological diagnosis of invasive candidiasis and to guide in the treatment of invasive fungal infections.

Methodology: The current project performs several phases related to the diagnosis and treatment of invasive candidiasis. In one of the phases, studying in vitro antifungal susceptibilities for supporting treatment of candidiasis, we have studied the activity of SCY-078, a new antifungal drug for treating infections caused by species of Candida resistant to conventional treatments, including Candida auris. This compound SCY-078 is a

new oral and intravenous drug for the treatment. We have evaluated the in vitro action of this drug SCY-078 and other antifungal drugs (azoles and echinocandins) against isolates of different Candida species isolated from blood cultures, such as Candida albicans, Candida parapsilosis, Candida tropicalis, Candida auris or Candida glabrata using the EUCAST method [2]. This method is the European protocol for studying the in vitro activity of antifungal drugs. EUCAST is a microdilution method for determining the Minimum Inhibitory Concentration (MIC) of the different antifungal agents and their usefulness for the treatment of invasive mycoses.

Conclusion: The main action of azoles is to inhibit lanosterol 14-α-demethylase coupled to cytochrome P-450. This action causes an alteration of fungal cell membranes increasing permeability and producing inhibition of cell growth and cell replication. Echinocandins inhibit 1,3-β-D-glucan synthetase, the enzymatic complex that forms β-D-glucan polymers in the cell wall of the fungus. The cell wall provides rigidity to the cell and its rupture causes the cell death. The compound CSY-078 is derived from enfumafungin (formerly MK-3118) and it is an inhibitor of the 1,3-β-D-glucan synthesis. This drug is the first in its class: triterpenic antifungal drugs. SCY-078 has demonstrated in vitro activity against many Candida species and against the multidrug-resistant pathogen Candida auris, which has been classified by the Centers for Disease Control and Prevention (CDC) as a Serious Threatens a global level for health In clinical development to treat candidemia and candidiasis [1,3,4]. During my stay, we have verified the excellent in vitro efficacy of the echinocandins caspofungin and micafungin and the new drug SCY-078 against many of the clinical isolates of Candida that were resistant to fluconazole. Moreover, SCY-078 was active against many Candida blood isolates with decreased susceptibility to caspofungin and micafungin.

In a recent article was described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative.

Protein degradation is a key function developed by organisms to remove damaged and abnormal proteins, preventing their accumulation, and serving at the same time to regulate cellular processes by removing enzymes and regulatory proteins that are no longer needed.1 This regulatory process can be achieved through two independent pathways: proteolysis in lysosome, or a ubiquitin-dependent process targeting unwanted proteins to proteasome. Due to its shattering function, proteasome has constituted an important therapeutic target to the control of different diseases such as malaria, cancer, multiple sclerosis, psoriasis, among others.2 Since this protein can be found both on the cell cytoplasm and nucleus, inhibitors developed to target it, must be able to cross the membrane lipidic barrier. Until now, it is unclear if transport involves simple passive diffusion or occurs via a yet unidentified transport system. In both scenarios, associations with the cell wall and the membrane are to be expected. Modeling the interaction of different inhibitors derivatives with the cell wall is not feasible because of its complicated and variable structure. However, it is possible to model and compare the interactions of different proven proteasome inhibitors with a lipid bilayer.

In this work, by using restrained (Potential of Mean Force - PMF) and unrestrained Molecular Dynamics simulations at the water/membrane interface, we have evaluated the membrane permeability rates of different proteasome inhibitors (available on the market and identified in our lab) and their configurational and positional preference in this mixed medium. Our results will allow us to compare the trafficking of the evaluated compounds through the cell membrane and to relate it with the proteasome inhibition efficiency.

Acknowledgements: We thank the Fundação para a Ciência e a Tecnologia for financial support through PTDC/QEQ-MED/7042/2014, UID/DTP/04138/2013, and SAICTPAC/0019/2015.

Description: MOL2NET Group: Is a scientific group for discussion of ideas related to the conference MOL2NET‬ International Conference on Multidisciplinary Sciences, 2015,05-10 Dec., MDPI Sciforum, HQ UPV/EHU, Bizkaia.

The group is expected to serve as discussion group both during the conference and inter-conference periods, to update participants with news about the conference and offer the possibility to the participant to make their FAQS and proposals and interact with the organization committee and other participants.MOL2NET Conference:

Dear Colleagues worldwide, I am glad to invite you to participate in our online conference using our social media. Conference: http://sciforum.net/conference/mol2net-1

* The scope includes, but is not limited to, Experimental ‪#‎Chemistry‬ (all branches), ‪#‎Medicine‬, ‪#‎Biomedical‬‪#‎Engineering‬, ‪#‎Materials‬, ‪#‎Nanosciences‬, ‪#‎Statistics‬, ‪#‎Data‬‪#‎Analytics‬, ‪#‎Computer‬ and ‪#‎Network‬‪#‎Science‬. * The conference is Totally Online, no physical presence is needed saving traveling costs. Proceedings will be Published Online, Open Access, Totally and Free of Charges (no cost). We accept both experimental and theoretical works in the areas mentioned.

*We call for short communications of preliminary unpublished results or synopsis, critical discussions, or mini-reviews of previously papers already published with 1-2 pages (including figures, tables, ref, etc.). *DOI numbers of the communications can be generated by the author uploading the paper to his/her own ResearchGate or Figshare profiles or by MDPI editorial.

In an effort to understand conditions triggering asthma episodes and therefore create a asthma risk index that might be valuable to both patients and medical practitioners, 6 different counties in Florida were chosen, 3 of them in the southeast region and 3 located in the central region. The number of cases at emergency rooms due to asthma and other respiratory conditions were provided by the Department of Health BRACE project and analyzed statistically looking for potential associations with weather and environmental conditions. Weather information was obtained from airports through Wolfram Language data mining interface, and environmental parameters (Ozone level and particulate matter) from the Environmental Protection Agency measuring stations. Correlation analysis was performed with both, linear and logistic models and using software RStudio. Additionally, ARIMA forecasting modeling was implemented within RStudio to predict future events based on previous records and compared with a Machine Learning approach.

During the last two decades academia and pharmaceutical industry made huge efforts to develop natural and synthetic proteasome inhibitors (PI). In 2003 FDA approved the pioneering dipeptidyl boronic acid derivative PI bortezomib for the treatment of refractory multiple myeloma (MM) and subsequently frontline therapy for MM. However, despite the enormous potential of PI, their use is still limited to certain types of blood cancer and shows severe side effects, dose limiting toxicity, peripheral neuropathy, limited activity in solid tumour and innate or acquired drug resistance.3

In this work, we have used Molecular Dynamics (MD) simulations to perform the first conformational and structural characterization of the human native 20S proteasome structure4. We focused our analysis on the three catalytic subunits well known for their proteolytic activity (b1, b2 and b5) and we further extended our study to additional MD simulations of three different point mutations in the b5 catalytic subunit, with recognized importance in PI’s resistance: Ala49Thr, Ala50Val and Cys52Phe. Hopefully, our studies will be able to shed the light on the structural key determinants that regulate the observed PI’s resistance in the different mutations, and ultimately use the acquired knowledge in the development of new alternative and efficient proteasome inhibitors.

Acknowledgements: We thank the Fundação para a Ciência e a Tecnologia for financial support PTDC/QEQ-MED/7042/2014, UID/DTP/04138/2013 and SAICTPAC/0019/2015.

Due to the clinical importance of the Dopamine D2-receptor (D2R) in several brain dysfunctions, the utilization of in silico models for drug development is a growing field of investigation. We provided a transparent and reproducible pipeline for creating a valid D2R model for small molecular docking studies. Furthermore, we suggested a binding pocket for the endogenous ligand of D2R, which was attained upon careful consideration of the available experimental data. Molecular docking studies with Dopamine, Quinpirole and Raclopride allowed also a better understanding of the binding pocket characteristics.

“Everything that living things do can be understood in terms of jigglings and wigglings of atoms.” Richard Feynman's remarks in the early 1960’s summarize what is today widely accepted, namely, that biological processes can be described by the dynamics of biomolecules. Molecular dynamics (MD) simulation, in this regard, is the main methodology employed in structural biology to explore the dynamical behavior of macromolecules at a microscopic level. Aided by MD, researchers have been able, for instance, to resolve atomic structures of multi-protein complexes from cryo-EM densities, thus unveiling the atomistic details of enzymatic mechanisms and characterize the binding of small molecules to proteins. To achieve all this, the capabilities of MD packages are constantly evolving, providing a multitude of complex simulation and analysis techniques, e.g., enhanced sampling and free energy calculations. Although applicable to a wide variety of research problems, a broader usage of MD is hindered by a steep initial learning curve imposed by nearly every MD software. To reduce this initial barrier and make the methodology more accessible to the general community of biomolecular researchers, we developed an intuitive tool named QwikMD (1), which assists the users in the preparation, execution, and analysis of biomolecular MD simulations. Among many other features, QwikMD automatically checks the initial structure for structural inconsistencies, facilitates structure manipulations such as point mutations and partial deletions, simplifies the protein insertion in lipid membranes and enables the visualization and analysis of MD simulations on the fly. The user-friendly graphical interface of QwiKMD allows the preparation of MD simulations in a point-and-click fashion, offering the user multiple MD protocols, such as unbiased MD simulations, Steered MD, MD Flexible Fitting (MDFF), and, most recently, hybrid QM/MM simulations. The latter exploits the recently developed VMD and NAMD interface to common quantum mechanics software packages. QwikMD facilitates performing MD simulations for nearly any user, novice or expert. While assisting the user, QwikMD ensures reproducibility of the results by recording all parameters and steps into two log files, one in a script-like format and another in a “methods section” format. QwikMD also serves as a learning tool, providing the theoretical background of the different MD protocols and options in many “info buttons”.

Computational methods have been widely used to characterize the catalytic mechanisms of several chemical systems namely enzymes. However, enzymes are studied using big chemical systems containing several thousands of atoms generating huge amounts of data that are hard to manipulate and analyze efficiently. Therefore, we developed molUP that is a user-friendly plugin for VMD to handle QM and ONIOM calculations performed using Gaussian software.

MolUP allows loading output files from Gaussian calculations and performs analysis concerning the structure of the chemical system as well as their energies and vibrational frequencies. Furthermore, molUP provides a graphical interface to manipulate the length of atomic bonds and the amplitude of angles and dihedral angles. Users can also easily choose which atoms belong to each ONIOM layer and the atoms that are free to move during a geometry optimization. At the end, molUP is capable of saving the new structure as a new Gaussian input file, ready to run a new calculation. Since molUP is a VMD extension, users can also benefit from the many features and resources available on VMD.

In order to demonstrate the potential of MolUP, we will also present the results that have been carried out in our research group regarding the catalytic mechanism of Serine HydroxyMethylTransferase (SHMT), using a QM/MM approach. SHMT is a pyridoxal-5'-phosphate (PLP)-dependent enzyme [1-3] that catalyzes the α-elimination of L-serine, where a methyl group is transferred from the substrate to a second cofactor, tetrahydrofolate (THF). The reaction occurs in six sequential steps from which the first one is the rate-limiting step with an activation barrier of 18.3 kcal/mol that closely fits the experimental kcat of 0.98±0.06 s-1 [4] (∆G‡ ≈ 18.2 kcal/mol). This first step involves the nucleophilic attack of nitrogen from THF to the β-carbon of the substrate, promoting the α-elimination of the CH2OH group of the substrate. The subsequent steps involve an intramolecular cyclization within the THF cofactor where the elimination product of the first step is incorporated, generating the 5,10-methyl-THF. At the end, the quinonoid intermediate (substrate + PLP) is protonated, producing glycine.